Cutaneous and subcutaneous calcifications (in general referred to as ectopic calcifications) complicate numerous diseases. They may be classified into dystrophic, metastatic, idiopathic, or iatrogenic calcifications, or into calciphylaxis.
Dystrophic calcifications are the result of local tissue abnormalities and grow in spite of normal plasma calcium and phosphorus levels. The main diseases that may develop due to these calcifications are: connective tissue diseases (scleroderma, CREST syndrome, juvenile dermatomyositis, lupus), cutaneous and subcutaneous infections (panniculitis), skin tumours (in particular pilomatricoma), certain congenital diseases (Elher-Danlos disease, Werner's syndrome, pseudo xanthoma elasticum).
Metastatic calcifications are, in contrast, the result of a disorder of calcium and phosphate metabolism (hypercalcemia and/or hyperphosphatemia). All diseases that cause these disorders may therefore contribute to the development of calcifications.
Idiopathic calcifications occur without tissue lesions or disorders of calcium and phosphate metabolism. The main known diseases in this group are tumoral calcinosis, scrotal calcifications as well as sub-epidermal calcified nodules.
Iatroqenic calcifications can occur following the injection of calcium or para-aminosalycylic acid. They have also been described following the use of calcium chloride saturated electrodes.
Calciphylaxis corresponds to the calcification of small sized blood vessels and of the sub-cutaneous adipose tissue. Most of the time secondary to chronic renal failure, and often associated with abnormalities of calcium and phosphate metabolism, however, it remains a separate entity given its specific pathophysiology and its particular evolutionary modalities.
Beyond the abnormal nature and unsightliness of their presence, these calcifications may cause complications in terms of functional capability (limitation of range of motion and joint function), with respect to pain (very painful nature of some calcifications, particularly in calciphylaxis) or on the trophic level (ischemia and necrosis of the cutaneous and subcutaneous tissues) that may—by such means—lead to additional infectious complications.
Although a number of treatments have been tried and reported (bisphosphonates, calcium channel blockers, probenecid) for these cutaneous and subcutaneous calcifications, to date there is no existing curative treatment for which efficacy has been demonstrated with a sufficient level of proof.
Sodium thiosulfate has been approved in the United States as an antidote for cyanide poisoning, and in the prophylaxis of cisplatin nephrotoxicity. Several publications have suggested a potential effect of sodium thiosulfate for the treatment of ectopic calcifications, and in particular of calciphylaxis. In the context of its marketing authorisation as an antidote for cyanide and in most of the published cases, sodium thiosulfate was administered preferably by the intravenous route. Certain articles report its use by oral administration. There is growing interest in the possible use of sodium thiosulfate by way of a systemic therapy for the treatment of calcifications caused for example by urolithiasis, nephrocalcinosis, tumoral calcinosis, calciphylaxis, or nephrogenic fibrosing dermopathies.
However prevailing concerns remain with respect to potential systemic side effects with these systemic routes (digestive disorders, metabolic acidosis, general bone related consequences, etc).
There is also an existing concentrated lotion containing 25% of sodium thiosulfate for cutaneous application, combined with acetylsalicylic acid, known by the trade name Versiclear®, which is authorised in the United States and is indicated in the treatment of the pityriasis versicolor. The presence of propylene glycol and isopropyl alcohol should be noted in its excipients.
The topical use of sodium thiosulphate could be advantageous, in particular for treating ectopic calcifications.
Two articles report the effects of sodium thiosulfate administration by cutaneous route. The first case concerns a 41-year old woman, suffering from systemic erythematosus lupus and presenting livedo reticularis with ulcers in her shins, the lesions being complicated by an infection, and a dystrophic calcification (Wolf et al. Arch Dermatol 2008; 144: 1560-2). A cutaneous treatment with sodium thiosulfate was administered twice a week, the treatment regimen being carried out in the physician's practice with application of 10% sodium thiosulfate compresses before dressing. This treatment therapy was complemented with the application of a topical corticosteroid around the wound. In addition, on a daily basis, the patient applied acetic acid compresses prior to the dressing. Her treatment was supplemented with suitable oral antibiotics. After six months, the superficial calcifications were dissolved, while at the same time the pains had progressively abated and it had been possible to reduce the antibiotics. Three months later, almost complete re-epithelialisation had occurred over the wound regions such that the antibiotic therapy could be stopped.
The second article reports two other cases treated by the cutaneous route. The first case concerns a 74 year old woman, suffering from osteo-arthritis, multiple sclerosis and pseudo-hypoparathyroidism, and presenting an ulcer on the leg with cutaneous calcium deposits and fibrosis (Bair et al, J Drugs Dermatol 2011; 10: 1042-4). The patient received topical applications of sodium thiosulfate 25% in zinc oxide applied twice daily over the wound region and the surrounding skin. This treatment was accompanied by the use of elasticated bandages, facilitating compression and elevation of the leg. The condition of the wound had improved significantly after five weeks, with good re-epithelialisation, and it had completely healed after 15 weeks of continuous therapy. The second case concerns a 81 year old man, with high serum calcium levels, mild renal failure and a calcified ulcer brought on by dystrophic calcification in the leg. This patient received the same treatment as the previous patient and was completely healed after 12 weeks of therapy.
Both of these published articles show that the cutaneous administration of sodium thiosulphate makes it possible to treat ulcers of the leg accompanied by cutaneous dystrophic calcifications. However, these articles do not give precise details pertaining to the formulation of sodium thiosulfate.
There are two main hypotheses to explain the effectiveness of thiosulfate. The first hypothesis would be chelation of the calcium attached to the blood vessels, the product thereof, the highly soluble calcium thiosulfate is then eliminated through the kidneys. The second mechanism would involve the antioxidant property of sodium thiosulfate (which possesses two unpaired electrons), which contributes to the restoration of endothelial function and the production of the enzyme eNOS (endothelial nitric oxide synthase).
Other hypotheses may also be considered. The sodium thiosulphate molecule indeed possesses two unpaired electrons, which are available for reacting with the reactive oxygen species generated during the endothelial dysfuntion that accompanies calciphylaxis. The production of a physiological antioxidant, the glutathione (GSH γ-glutamyl-cysteinyl-glycine), was observed during this reaction. Sodium thiosulfate could also be the cause of the emission of H2S, a neurovascular modulator gas, from a variety of reactions involving thiol compounds with enzymatic trans-sulfuration reactions from the endogenous substrate that L-cysteine represents. This molecule, H2S, is known as being endowed with vasodilator, analgesic and anti-inflammatory properties that may explain the pain relief effects observed in all of the cases reported. The improvement of endothelial dysfunction may also explain the intense and rapid relief of neuropathic pains reported.
The chelating properties of sodium thiosulfate towards calcium would be responsible for its action on the subcutaneous calcifications that develop in the form of painful plaques or nodules, the action taking place over a long-term, requiring months of treatment, but the real occurrence of which is objectively demonstrated by physical examination (palpation) and imaging.
The inventors have developed a pharmaceutical composition comprising sodium thiosulfate dispersed in a hydrophile-in-lipophile emulsion. They have also administered this preparation by the cutaneous route to a 12 year old boy with a large sized subcutaneous calcification on the posterior surface of his left elbow, which limited the mobilisation of the elbow. The patient applied topically every evening about 1 to 1.5 gram of the pharmaceutical composition having a sodium thiosulfate content amounting to 10% (by weight). The patient received no other type of treatment during his treatment with sodium thiosulfate. After six months of treatment, the medical examination showed a dramatic improvement, with no visible subcutaneous lesion and the mobilisation of the elbow being restored to the normal state. In addition, no systemic or local side effect was observed. These data demonstrate that sodium thiosulfate can be used for topical administration as a means of providing an effective and safe treatment of soft tissue calcifications.
Consequently, the invention thus relates to the use of sodium thiosulfate intended for topical administration for the treatment of an ectopic calcification and/or of the consequences thereof in an individual, who may or may not be receiving any other preventive or therapeutic, pharmacological or mechanical medication for calcifications. The invention also relates to the pharmaceutical composition comprising sodium thiosulfate dispersed in a hydrophile-in-lipophile emulsion developed by the inventors, as well as the method for preparing this pharmaceutical composition.